Titel: A 13C breath test for in vivo determination of the metabolic flux in medium-chain acyl-coenzyme A dehydrogenase deficiency
Sonstige Titel: Etablierung eines 13C-Atemtest zur Bestimmung der aktuellen Stoffwechsellage bei Patienten mit einem Mangel des Enzyms mittelkettige Acyl-Coenzym A-Dehydrogenase
Sprache: Englisch
Autor*in: Neumann, Friederike Sophia
Schlagwörter: Medium chain acyl-coenzyme A (CoA) dehydrogenase deficiency; Mitochondrial fatty acid oxidation; Metabolic flux; Activity in lymphocytes; Acylcarnitine levels; 13C-phenylpropionic acid breath test
Erscheinungsdatum: 2020
Tag der mündlichen Prüfung: 2021-02-01
Zusammenfassung: 
Background: Deficiency of medium chain acyl-coenzyme A (CoA) dehydrogenase (deficient enzyme: MCAD, disease: MCADD) leads to a reduced ability to catalyze C6 to C10 straight-chain acyl-CoA as the initial step of the mitochondrial fatty acid oxidation. This pathogenic mechanism impairs the energy supply to peripheral tissues predisposing affected individuals to become symptomatic in situations of decreased oral carbohydrate intake. Patients are at risk of hypoketotic crises with hypoglycemia, which can progress to coma and sudden death. MCADD is detected by medium-chain acylcarnitine profiles and disease severity is estimated by ex vivo enzyme activity analysis in lymphocytes. However, the assessment of the current metabolic state in MCADD patients is unsatisfactory.

Methods: The in vivo metabolic flux was analyzed by using a 13C breath test. Following oral application of 13C-phenylpropionic acid (13C-PPA) as substrate for the MCAD enzyme, 13CO2 was determined in exhaled air for 180 minutes. Breath test measurements were accompanied by the analysis of acylcarnitine profiles and MCAD enzyme activity in lymphocytes. The study population consisted of 11 patients homozygous for the variant p.[Lys329Glu];[Lys329Glu], 1 patient homozygous for the variant c.[244insT*104];[244insT*104], 13 compound heterozygous patients, 9 heterozygous carriers, and 6 healthy controls.

Results: Results of C8/C10 ratio and MCAD activity in lymphocytes revealed a strong correlation to breath test results in our study cohort (Rank correlation analysis by Spearman’s correlation coefficient). Cutoff values of 2.36 for C8/C10 ratio, 35.57 % of wild type for MCAD activity in lymphocytes and 28.6 % for cumulative 13C recovery rate in breath test were calculated to distinguish between affected and healthy participants. Only the 13C breath test delivered a second significant cutoff value of 20.3 % to divide between severely and moderately affected patients.

Discussion: We show that an in vivo metabolic flux analysis by 13C-PPA breath test promises to serve as an additional tool to determine the current metabolic state in MCADD patients. Hence, we conclude that the combination of all 3 diagnostic tools (C8/C10 ratio, MCAD activity in lymphocytes, 13C-PPA breath test) allows favorable functional testing at multiple levels.
URL: https://ediss.sub.uni-hamburg.de/handle/ediss/8848
URN: urn:nbn:de:gbv:18-ediss-90429
Dokumenttyp: Dissertation
Betreuer*in: Gersting, Sören
Enthalten in den Sammlungen:Elektronische Dissertationen und Habilitationen

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